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BBB webinar: Arnaud Mourier

Malate dehydrogenase 2 (MDH2) is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle

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Arnaud Mourier
Institute of Cellular Biochemistry and Genetics (IBGC), University of Bordeaux, and French National Centre for Scientific Research (CNRS), Bordeaux, France

Mitochondria are best known as the ‘powerhouses’ that supply eukaryotes with energy in the form of ATP. Beyond ATP synthesis, mitochondrial maintenance of NAD(P)H/NAD(P)+ redox cofactor balance is of paramount importance for numerous mitochondrial and cytosolic metabolic processes. However, the specific metabolic regulations allowing mitochondrial respiration to prioritize NADH oxidation in response to high NADH/NAD+ redox stress have not been elucidated. The recent discovery that complex I (NADH dehydrogenase), and not complex II (succinate dehydrogenase), can assemble with other respiratory chain (RC) complexes to form functional entities called respirasomes, led to the assumption that this supramolecular organisation could favour NADH oxidation. However, the metabolic and physiological roles played by the respirasomes is much debated.

Characterization of metabolically active heart and liver mitochondria demonstrates that unexpectedly, the RC systematically favours electrons provided by the ‘respirasome-free’ complex II. However, our results demonstrate that succinate driven respiration is tightly controlled by oxaloacetate (OAA) levels, and that OAA feedback inhibition of complex II rewires RC fuelling, increasing NADH oxidation capacity. This new regulatory mechanism synergistically increases RC’s NADH oxidative capacity and rewires MDH2 driven anaplerosis of the TCA cycle, preventing malate production from succinate to favour oxidation of cytosolic malate. The MDH2-mediated rewiring of the fuelling of mitochondrial RC and TCA anaplerosis mechanically increases the capacity of the RC to indirectly maintain the cytosolic redox (NADH/NAD+) balance

Chairperson: Gro Vatne Røsland, Department of Biomedicine